Interleukin 10 deficiency exacerbates halothane induced liver injury by increasing interleukin 8 expression and neutrophil infiltration.
The prediction and prevention of drug-induced liver injury (DILI) have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. Using a newly established DILI model induced by halothane, we found increased liver damage susceptibility in interleukin 10 (IL-10) knockout (KO) mice. Extensive neutrophil infiltration and chemoattractant factor interleukin 8 (IL-8) expression in IL-10 KO mice were observed after halothane administration. The elevation of IL-8 expression was NF-kappaB- and P38 MAPK-dependent. In addition, increased signal transducer and activator of transcription factors (STAT) 1 and STAT3 were observed in halothane treated IL-10 KO mice. Exogenous IL-10 treatment protected susceptible mice from halothane induced liver injury (HILI). In conclusion, IL-10 deficiency increases susceptibility to HILI and increased IL-8 expression as well as neutrophil infiltration may be responsible for this phenomenon.
Feng
Dechun
D
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Wang
Ying
Y
Xu
Yan
Y
Luo
Qingqiong
Q
Lan
Bin
B
Xu
Lingyun
L
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018450:Disease Progression; D005786:Gene Expression Regulation; D006221:Halothane / Q000633:toxicity*; D016753:Interleukin-10 / Q000172:deficiency* / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D000410:Alanine Transaminase; D048051:p38 Mitogen-Activated Protein Kinases; D006221:Halothane